Comprehensive bioinformatics study reveals targets and molecular mechanism of hesperetin in overcoming breast cancer chemoresistance

Abstract: The effectiveness of chemotherapy in breast cancer treatment can be increased using a combinatorial agent. Hesperetin has been reported to increase the sensitivity of doxorubicin in breast cancer cells; however, the underlying molecular mechanism remains unclear. This present study was conducted to identify the potential target and molecular mechanism of hesperetin in circumventing breast cancer chemoresistance using a bioinformatics approach. Microarray data obtained after hesperetin treatment in the NCI-60 cell line panel collection were retrieved from the COMPARE public library. These data were then compared with the list of the regulatory genes of breast cancer resistance obtained from PubMed and further analyzed for gene ontology and KEGG pathway enrichment, as well as protein�protein interaction network. A Venn diagram of COMPARE microarray data and the gene list from PubMed generated 56 genes (potential therapeutic target genes/PTTGs). These PTTGs participate in the biological process of the JAK-STAT cascade and are located in the nucleus, exert a molecular function in protein serine/threonine kinase activity, and regulate the erbB signaling pathway. Drug association analysis demonstrated that both hesperetin and the erbB receptor inhibitors, i.e., monoclonal antibody and tyrosine kinase inhibitor, target the same mRNA expression. Furthermore, results of the molecular docking study revealed that hesperetin is a promising inhibitor that targets ABL1, DNMT3B, and MLH1 due to the similarity of binding properties with its native ligand. In conclusion, the possible pathways and the regulatory genes identified in this study may offer new insights into the mechanism by which hesperetin overcomes breast cancer chemoresistance. A combinatorial therapy with hesperetin targeting ABL1, DNMT3B, and MLH1 may be effective in circumventing chemoresistance in breast cancer.